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Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4) is mediated by GSK-3? signaling in rat cortical neuroblasts.

ABSTRACT: Ingestion of ethanol (ETOH) during pregnancy induces grave abnormalities in developing fetal brain. We have previously reported that ETOH induces programmed cell death 4 (PDCD4), a critical regulator of cell growth, in cultured fetal cerebral cortical neurons (PCNs) and in the cerebral cortex in vivo and affect protein synthesis as observed in Fetal Alcohol Spectrum Disorder (FASD). However, the mechanism which activates PDCD4 in neuronal systems is unclear and understanding this regulation may provide a counteractive strategy to correct the protein synthesis associated developmental changes seen in FASD. The present study investigates the molecular mechanism by which ethanol regulates PDCD4 in cortical neuroblasts, the immediate precursor of neurons. ETOH treatment significantly increased PDCD4 protein and transcript expression in spontaneously immortalized rat brain neuroblasts. Since PDCD4 is regulated at both the post-translational and post-transcriptional level, we assessed ETOH's effect on PDCD4 protein and mRNA stability. Chase experiments demonstrated that ETOH does not significantly impact either PDCD4 protein or mRNA stabilization. PDCD4 promoter-reporter assays confirmed that PDCD4 is transcriptionally regulated by ETOH in neuroblasts. Given a critical role of glycogen synthase kinase 3? (GSK-3?) signaling in regulating protein synthesis and neurotoxic mechanisms, we investigated the involvement of GSK-3? and showed that multifunctional GSK-3? was significantly activated in response to ETOH in neuroblasts. In addition, we found that ETOH-induced activation of PDCD4 was inhibited by pharmacologic blockade of GSK-3? using inhibitors, lithium chloride (LiCl) and SB-216763 or siRNA mediated silencing of GSK-3?. These results suggest that ethanol transcriptionally upregulates PDCD4 by enhancing GSK-3? signaling in cortical neuroblasts. Further, we demonstrate that canonical Wnt-3a/GSK-3? signaling is involved in regulating PDCD4 protein expression. Altogether, we provide evidence that GSK-3?/PDCD4 network may represent a critical modulatory point to manage the protein synthetic anomalies and growth aberrations of neural cells seen in FASD.

SUBMITTER: Riar AK

PROVIDER: S-EPMC4024002 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4) is mediated by GSK-3β signaling in rat cortical neuroblasts.

Riar Amanjot Kaur AK Narasimhan Madhusudhanan M Rathinam Mary Latha ML Vedpathak Dhanashree D Mummidi Srinivas S Henderson George I GI Mahimainathan Lenin L

PloS one 20140516 5

Ingestion of ethanol (ETOH) during pregnancy induces grave abnormalities in developing fetal brain. We have previously reported that ETOH induces programmed cell death 4 (PDCD4), a critical regulator of cell growth, in cultured fetal cerebral cortical neurons (PCNs) and in the cerebral cortex in vivo and affect protein synthesis as observed in Fetal Alcohol Spectrum Disorder (FASD). However, the mechanism which activates PDCD4 in neuronal systems is unclear and understanding this regulation may ...[more]

PMID: 24837604

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Project description:Background:The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose:The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods:We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15-98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results:We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion:These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.

Dataset Information

Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4) is mediated by GSK-3? signaling in rat cortical neuroblasts.

Publications

Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4) is mediated by GSK-3β signaling in rat cortical neuroblasts.

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